Time-resolved single-cell analysis of Brca1 associated mammary tumorigenesis reveals aberrant differentiation of luminal progenitors

One of the major hurdles for the early detection of cancer is our poor understanding of tumour initiating events. Historically, cancer research has focused on histological and molecular characterisation of established tumours, which has led to the identification of hundreds of putative driver mutations. It is currently unclear how these genetic aberrations impact the cell state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) for example has been shown to arise from luminal progenitor cells yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that the perturbation of Brca1/p53 in luminal progenitors induces an aberrant alveolar differentiation pre-malignancy. Unlike alveolar differentiation occurring during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Our experimental approach has allowed us to further identify responses in the stromal and immune cell compartments during the early steps of tumourigenesis. The data in this repository contains the human bulk RNA-sequencing that was presented as part of this study.